%0 Journal Article
%T CRISPR-Cas9 Screening and Multi-Omics Reveal the CHD7–ANGPT1 Axis as a Driver of Multidrug Resistance in Acute Myeloid Leukemia
%A Emma Wilson
%A Frederik De Jong
%A Lara Peters
%J Interdisciplinary Research in Medical Sciences Specialty
%@ 3062-4401
%D 2025
%V 5
%N 2
%R 10.51847/ck7MScPl6m
%P 131-149
%X Acute myeloid leukemia (AML) is an aggressive hematological cancer and ranks among the most frequent leukemias observed in adults. Although new targeted treatments have recently been developed and approved, the emergence of drug resistance continues to present a serious therapeutic barrier. This investigation utilized an unbiased CRISPR-Cas9 gene knockout screen in AML cell lines to discover unrecognized factors contributing to resistance against the approved FLT3 inhibitor gilteritinib. The screen pinpointed chromodomain helicase DNA binding protein 7 (CHD7) as a previously unidentified modulator of therapeutic resistance. Notably, inactivation of CHD7 not only produced resistance to FLT3-targeted agents but also generated cross-resistance to a wide array of drugs, such as venetoclax and daunorubicin (DNR). Integrated transcriptomic and proteomic analyses indicated that deletion of CHD7 elevates angiopoietin-1 (ANGPT1) levels, which promotes resistance by stimulating the PI3K/AKT and MAPK/ERK pathways. Importantly, reducing ANGPT1 expression through genetic knockdown or blocking its receptor TIE2 with pharmacological agents partially reversed drug insensitivity in cells lacking CHD7. Overall, these results highlight the CHD7-ANGPT1 signaling axis as a novel contributor to multidrug resistance in AML. Preclinical evidence additionally supports the potential of combining targeted AML therapies with TIE2 inhibitors as an effective means to counteract drug resistance.
%U https://galaxypub.co/article/crispr-cas9-screening-and-multi-omics-reveal-the-chd7angpt1-axis-as-a-driver-of-multidrug-resistanc-9uv8fivkk7dv4js